Bis(maltolato)oxovanadium compositions for the treatment of elevated blood sugar

ABSTRACT

There are provided vanadium compositions for use in the treatment of hypertension, obesity and diabetes, in particular improved oral compositions comprising oxovanadium (IV) chelates of monoprotic, bidentate oxygen, oxygen and oxygen, nitrogen coordinating ligands especially kojic acid and maltol.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.08/040,113, filed Mar. 30, 1993, now abandoned, which is acontinuation-in-part of application Ser. No. 07/767,510 filed Sep. 30,1991, now U.S. Pat No. 5,300,496, and of the U.S. designation ofInternational Patent Application No. PCT/EP92/02235 filed Sep. 29, 1992.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions useful forlowering blood sugar, lowering blood pressure and suppressing appetitein mammals, and to a method of lowering blood glucose, treatinghypertension and suppressing appetite.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a mammalian condition in which the amount ofglucose in the blood plasma is abnormally high. This condition can belife-threatening and high glucose levels in the blood plasma(hyperglycemia) can lead to a number of chronic diabetes syndromes, forexample, atherosclerosis, microangiopathy, kidney disorders, renalfailure, cardiac disease, diabetic retinopathy and other oculardisorders including blindness.

It is a disease of some complexity, as indicated by its effect on alarge number of important functions of the body. There are large numbersof sufferers. For example, in the late 1980's over 2.6 million people inthe United States were diabetics who were taking insulin by injectiondaily. Approximately an equal number of diabetics were taking oralhypoglycemic agents and another 2 to 3 million people were controllingthe disease by dietary methods alone. It is estimated there are severalmillion people in the U.S. who are undiagnosed diabetics.

In non-diabetics, plasma glucose level is maintained automatically in acomplex procedure that involves, inter alia, the hormone insulin. Indiabetes, external intervention is needed. Treatment of diabetics is nowcarried out using several drugs. Insulin is the mainstay of treatment;it replaces the natural hormone produced in the pancreas. In diabetics,insulin is not produced in sufficient quantities, or the body becomestolerant to insulin and requires more than normal amounts to produce thenecessary effect.

Insulin must be given by injection. Insulin cannot be administeredorally as it is decomposed before or during passage through thegastrointestinal tract. It is difficult to determine the exact amountrequired. This can result in overdoses, leading to hypoglycemia, and ininadequate doses, leading to poor control of the disease and thedevelopment of secondary complications.

Oral diabetes medications (such as sulphonylureas and biguanides) areavailable. As with insulin it can be difficult to obtain a correct dose.There has been shown to be a difficulty with the sulphonylureas incorrectly regulating blood glucose levels. Hypoglycemic episodes oftenoccur in elderly patients. The biguanides lower blood glucose, but canproduce side effects, such as lactic acidosis, which can be fatal.

Sodium orthovanadate has been found to be a potent inhibitor of Na⁺ -K⁺ATPase. It has also been found that vanadate (vanadium (V)) taken up bythe red blood cells was reduced to vanadium (IV) in the form of vanadylion VO²⁺ in the cytoplasm. Since this work, there has been interest inthe effects of vanadium, mostly as vanadate, on glucose metabolism anduptake into cells. A natural outgrowth of this work has been the studyof vanadium and diabetes. (See J. Biol. Chem. 252: 7421-7423 (1977), J.Biol. Chem. 254:1781-1784 (1979) and Diabetes 39: 1-5 (1990)).

The insulin-like effect of the vanadate ion (VO₄ ³⁻) in vitro has beenknown since 1980 (see Nature 284: 556-558 (1980)) when it was shown thatthe insulin-like stimulation of glucose oxidation in rat adipocytes wasdue to the vanadyl ion. In 1985, McNeill et al. (Science 227: 1474-1477(1985)) reported that vanadate, when administered in drinking water,decreased the elevated blood glucose and prevented the depression ofcardiac performance in rats made diabetic with streptozotocin (STZ).Subsequently, there has been interest in the insulin-mimetic effects ofboth vanadate and vanadyl since Sakurai et al. showed that vanadate isreduced in vivo to vanadyl (Biochem. Biophys. Res. Comm. 96:293-298(1980)).

Vanadate however has the drawbacks that it is poorly absorbed from thegastrointestinal tract to the blood and that it is toxic. Administeredconcentrations must be close to the toxic level if the insulin-mimeticeffects in mammals are to be achieved.

Work by McNeill et al. (see Am. J. Physiol 257: H904-H911 (1989),Metabolism 38:1022-1028 (1989), Diabetes 38: 1390-1395 (1989) and Can.J. Physiol & Pharmacol. 68: 486-491 (1990)) has shown that vanadyladministered orally as vanadyl sulfate also lowers blood glucose andblood lipids in STZ diabetic rats and prevents secondary complicationsof diabetes such as cataracts and cardiac dysfunction. Vanadyl sulfateis less toxic than the vanadate form of vanadium but is also poorlyabsorbed. There have been attempts to modify the biological uptake ofvanadium by changing the chemical form in which it is supplied fromeither vanadate (VO₄ ³⁻) or vanadyl sulfate (VOSO₄. (H₂ O)_(x)). In thisregard, the use of various vanadate:peroxide reaction products asinsulin mimics has been suggested by Posner et al. (See U.S. Pat. No.4,882,171, U.S. Pat. No. 5,069,913 Biochem. Biophys. Res. Comm. 147:259-266 (1987) and J. Biol. Chem. 262: 8252-8256 (1987)).

The use, for the oral treatment of diabetes, of a cysteine complex ofvanadium of the formula ##STR1## is described in EP-A-305264. The use ofvanadium cysteine complexes was also reported in JP-A-2/292217 byKomatsu et al. However these cysteine complexes are generally not wellcharacterised and only poorly water soluble and thus are not well suitedto oral administration. Moreover their utility is further diminished bythe relatively long delay between administration and the onset of ablood sugar lowering effect. Komatsu et al. (supra) also proposed theuse of a pentane-2,4-dione complex of the vanadyl ion. This however istoxic at effective doses and accordingly is also not well suited to oraladministration.

Accordingly, there remains a need for compositions useful in thetreatment of diabetes with vanadium and we have found that certainbidentate, monoprotic chelants, with vanadium co-ordinating oxygen,sulphur or nitrogen atoms form vanadium complexes particularly suitablefor therapeutic use, especially for oral administration.

SUMMARY OF THE INVENTION

Thus viewed from one aspect the invention provides a pharmaceuticalcomposition, preferably in a form adapted for administration into thegastrointestinal tract, comprising at least one physiologicallyacceptable carrier together with a physiologically tolerable vanadiumcomplex of a bidentate monoprotic chelant, preferably a water-solublechelant, capable of chelating vanadium to form a five- or six-memberedunsaturated vanadium-containing ring, said ring containing at least twofurther heteroatoms besides vanadium, and said ring if six-memberedcontaining vanadium-coordinating oxygen and nitrogen ring heteroatoms.

The five- or six-membered rings formed by chelation of vanadium by thebidentate monoprotic chelant used according to the invention preferablyinvolve oxygen, sulphur or nitrogen coordination of the vanadium,particularly oxygen, oxygen or nitrogen, oxygen coordination.

DETAILED DESCRIPTION

Particularly suitably the five-membered ring forming chelants usefulaccording to the invention may be represented by the formula I ##STR2##(where X¹ and X³ are independently oxygen, sulphur or NX⁶, preferablyoxygen or NX⁶ ; X² is nitrogen or CX⁷ ; X⁴, X⁵, X⁶ and X⁷ areindependently non-labile protons or optionally substituted alkyl, aryl,aralkyl or alkaryl or at least one pair of X⁴ to X⁷, preferably X⁴ andX⁵, together with the intervening atoms represents an optionallysubstituted, saturated or unsaturated homo or heterocyclic ring, orwhere X¹ represents a NX⁶ group X⁴ may represent a group X⁸ H where X⁸is oxygen or sulphur; and one X¹ or X⁸ attached proton, preferably an X¹attached proton, is labile).

Thus, for example, the chelant used according to the invention may be anα-amino acid (other than cysteine), a hydroxamate or thiohydroxamate anα-hydroxy-carbonyl, such as for example an α-hydroxy-pyridinone or anα-hydroxypyrone, eg. maltol or kojic acid.

The six-membered ring forming chelants useful according to the inventionpreferably coordinate vanadium to form a ring carrying two fused five orsix-membered homo or heterocyclic rings containing 0, 1 or 2 heteroatomsselected from O, N and S and are preferably of formula II ##STR3## whereA and B are five-, six- or seven-membered rings containing 0, 1 or 2ring heteroatoms selected from O, N and S and optionally substituted byX⁴ groups or oxo, thio or =NX⁴ groups where X⁴ is as defined above.

In formula II above, the A and B rings are preferably optionallysubstituted 1,2-phenylene, oxazolin-2-yl or thiazolin-2-yl groups,especially groups of formulae ##STR4## where X⁴ is hydrogen or anoptionally hydroxylated C₁₋₄ alkyl group

Where the chelant comprises a homo or heterocyclic ring, unlessotherwise specified this will preferably be a 5, 6 or 7 membered ringcontaining 0, 1, 2 or 3, especially 0, 1, or 2 heteroatoms, selectedfrom O, N and S. Each aryl group is preferably phenyl or naphthyl,especially phenyl; each alkyl or alkenyl group or moiety preferablycontains 1 to 6 carbon atoms, especially 1 to 4; and the optionalsubstituents, which do not include thiol groups, are preferably selectedfrom hydroxy, alkoxy, oxo, amide and amine groups, and alkyl groupscarrying such substituents. Such groups may be selected for theirability to enhance the hydrophilicity or lipophilicity of the complex orto enable the complex to be conjugated to a further species, eg. abiomolecule, protein, polymer, etc.

Particularly suitable chelants of formula I and II include thehydroxamates of formula III and IV ##STR5## the α-hydroxy-pyridinones offormula V ##STR6## the α-hydroxypyrones of formula VI ##STR7## theα-amino acids of formula VII ##STR8## the hydroxy carbonyls of formulaeVIII and IX ##STR9## the thiohydroxamates of formulae X and XI ##STR10##and the 2-oxazolin-2-yl-phenols and 2-thiazolin-2-yl-phenols of formulaeXII and XIII ##STR11## (where R¹ to R²⁵ are hydrogen or optionallysubstituted, e.g. hydroxylated C₁₋₄ alkyl).

Especially preferred as chelants of formula I are maltol and kojic acid##STR12## Chelants of this type are known from the literature (see forexample Matsuba et al Inorg. Chem. 27: 3935-3939 (1988)) or may beproduced from known starting materials by conventional techniques.

The oxazolinylphenol and thiazolinylphenol chelants are also especiallypreferred due to the stability to oxidation in air of the resultingvanadium complexes.

Examples of hydroxamate chelants may be found in J. Ind. Chem. Soc.44:369-376 (1967) and Inorg. Chem. 28:4399-4406 (1989).

Thus for example many hydroxamate chelants are known. These can readilybe prepared by reaction of an acyl halide with a substitutedhydroxylamine

    RCOX+R'NHOH→RCON(OH)R'

Many of the vanadium chelates with ligands of formula I might beprepared from maltol or maltol derivatives in a one-pot synthesisanalogous to that described for gallium, aluminium and indium complexesby Zhang et al in Can. J. Chem. 67: 1708-1710 (1989). Thus ##STR13##

The direct electrochemical preparation of a vanadyl maltol compound wasreported in J. Coord. Chem. 8: 27-33 (1978). The biological activity wasnot examined and the structural formula was not determined but the datasuggested it to be: ##STR14##

Alkoxo-oxovanadium (V) derivatives of the maltolate anion have beenknown since the 1960's, but again the biological activity was notexamined (see Z. Anal. Chem. 203:257-260 (1964)).

The vanadium complex used according to the invention is preferably acomplex of vanadium (III), (IV) or (V), especially (IV) or (V), with aligand as described above, especially preferably a complex VOL₂, VO₂ L₂or VOL₂ (OR²⁶) where LH is a chelant as described above and R²⁶ is anoptionally substituted alkyl, aryl, aralkyl or alkenyl group (where suchgroups are as defined above), preferably such a group is substituted byat least one hydroxyl group.

Where LH is a chelant which forms a five membered ##STR15## ring, theseVOL₂ and VOL₂ (OR²⁶) complexes, can schematically be represented by theformulae ##STR16## where R" is the remainder of the chelating group.

In general, backbone and ring substituents on the vanadium coordinatingligands are selected for their solubilizing effect. Desirably thevanadium complexes used according to the invention will be neutrallycharged overall, water soluble (eg. capable of forming an at least 0.1mM solution, preferably an at least 0.2 mM solution), orally absorbable(preferably with significant gastro-intestinal absorption), and havemoderate to high complex stability (eg. with ligand binding constantslog β₂ ≦2 to 30, preferably 6 to 20).

Particularly preferred compounds include the maltol and kojic acidcomplexes bis(maltolato)oxovanadium(IV) and bis(kojato)oxovanadium(IV).

Vanadium complex formation may be effected by conventional metallationor transmetallation techniques, eg. by mixture in solution of a solublevanadium salt with the chelant or a salt or weaker complex thereof.

We have surprisingly found that, besides being effective in thetreatment of diabetes by virtue of its blood sugar lowering effect,vanadium has appetite suppressing and antihypertensive effects.

Accordingly, viewed from a further aspect, the invention provides theuse of a physiologically tolerable vanadium compound, preferably a V(V)or V(IV) compound, for the manufacture of an antihypertensive or bloodpressure lowering agent.

Viewed from a further aspect the invention provides the use of aphysiologically tolerable vanadium compound, preferably a V(V) or V(IV)compound, for the manufacture of an appetite suppressing agent.

Viewed from a yet further aspect the invention provides a method oftreatment of the human or non-human mammalian body to combat elevatedblood pressure which method comprises administering to said body, forexample parenterally or into the gastrointestinal tract, aphysiologically tolerable vanadium compound, preferably a water solublecompound.

Viewed from a still further aspect the invention provides a method oftreatment of the human or non-human mammalian body to suppress appetite,eg. for cosmetic purposes or in the treatment of illness, dysfunction orobesity, which method comprises administering to said body, for exampleparenterally or into the gastrointestinal tract, a physiologicallytolerable vanadium compound, preferably a water soluble compound.

The vanadium compounds useful according to the invention areconveniently oxovanadium chelates but the sulphur and nitrogenanalogues, i.e. VS, V.tbd.N and VNR²⁷ (where R²⁷ is as defined for R¹ toR²⁶) may also be used according to the invention in treatment to lowerblood sugar, to suppress appetite or to combat hypertension.

The vanadium compounds can be given by conventional administrationroutes, eg. oral, rectal, intravenous, subcutaneous, intraperitoneal,transdermal, etc. However oral administration is preferred.

In the treatment of hypertension and in the appetite suppressiontreatment it is especially preferred that the vanadium compound be onewhich can be taken up by the body following administration into a bodyorifice, particularly oral or rectal administration, and it isespecially preferred to use water-soluble vanadium (IV) or vanadium (V)compounds. While the use of the compounds described earlier for thetreatment of diabetes are of course especially preferred, otherphysiologically tolerable inorganic salts or organic salts or complexesof vandium can be used. In this regard reference may be made to thevanadium peroxide compositions of Posner (see U.S. Pat. No. 4,882,171and U.S. Pat. No. 5,069,913), the vanadyl complexes of Lazaro (such asthe cysteine complex Naglivan, see U.S. Pat. No. 5,023,358), vanadylsulphate, sodium orthovanadate, vanadyl complexes with monoproticbidentate 2,4-diones, and the vanadyl complexes of Komatsu (seeJP-A-2/292217).

The invention thus also provides pharmaceutical compositions for use inthe treatment of diabetes and hypertension and pharmaceuticalcompositions for use in suppressing appetite containing at least onephysiologically acceptable vanadium source as discussed above togetherwith at least one physiologically acceptable carrier or excipient.

The compositions for use according to the invention may be inconventional administration forms, eg. capsule, tablet, coated tablet,solution, suspension, syrup, transdermal or suppository, andconventional formulation aids and excipients may be used, eg. viscositymodifiers, buffers, flavouring agents, suspension agents, stabilizers,excess ligand, and other additives.

For transdermal administration the vanadium complexes will preferablyinclude lipophilic and hydrophilic groups to achieve the desired watersolubility and transport properties. For iontophoretic administration,the vanadium complex should of course not be charge neutral and thecounterions will preferably be such as to generate water or an insolublesalt at the electrode.

The compositions of the invention may also contain other therapeuticallyactive agents, eg. antidiabetic, antihypertensive and appetitesuppressing agents. In this regard, special mention may be made of themetal compounds considered to be useful in the treatment of diabetes,e.g. MgCl₂ and chromium picolinate. Vanadium may of course be used incombination therapy with insulin, e.g. in the treatment of Type Idiabetes.

The combined use of vanadium and other antidiabetic agents has theadvantages that the required dosages for the individual drugs would belower and the onset and duration of effect of the different drugs wouldbe complimentary. Thus viewed from a further aspect the inventionprovides a method of combined therapy of diabetes comprisingadministering to a diabetic mammalian subject a blood glucose loweringcombination of a physiologically tolerable vanadium compound and afurther antidiabetic drug.

In the combined therapy, the different active agents can be deliveredtogether or separately, and simultaneously or at different times withinthe day. Moreover the compounds may be administered by any convenientand effective route, eg. by injection, orally, rectally ortransdermally. Preferably administration will be orally or transdermallyand also preferably the different agents will be administeredsubstantially simultaneously, preferably as a composition containingboth agents.

The combination of vanadium and other antidiabetic agents is novel andsuch compositions form a further aspect of the invention. Viewed fromthis aspect the invention provides a pharmaceutical compositioncomprising a physiologically tolerable vanadium compound, preferably acomplex according to the invention, together with a furtherphysiologically tolerable antidiabetic drug.

Depending on the animal and condition being treated and on theadministration route the vanadium compounds will generally beadministered in dosages of 0.00035 to 600 mg V/kg bodyweight per day.The range is broad since in general the efficacy of a therapeutic effectfor different mammals varies widely with doses typically being 20, 30 oreven 40 times smaller (per unit bodyweight) in man than in the rat.Similarly the mode of administration can have a large effect on dosage.Thus for example oral dosages in the rat may be ten times the injectiondose. As a result, the preferred range for rats is 0.1 to 300 mgV/kg/day while for man it may be 0.0007 to 2.0 mg V/kg/day.

The compositions, if in solution preferably contain the vanadiumcompounds at concentrations which provide the effective dose either innormal daily water intake or as a daily solution supplement(s) or tabletthat provides the correct dose.

The vanadium compounds will generally be administered in dosages of 10⁻⁵to 1000 mg V/kg/day bodyweight, especially 10⁻⁴ to 500 mg V/kg/day,particularly up to 400 mg V/kg/day and most especially up to 300 mgV/kg/day. Dosages for humans by oral administration will generally liein the range 10⁻⁴ to 200 mg V/kg/day, preferably in the range 2.5 to2000 μg V/kg/day, e.g. 5 to 500 μg V/kg/day especially 5 to 200μgV/kg/day and by injection in the range 10⁻⁴ to 100 mg V/kg/day,preferably in the range of 0.1 to 50 μg V/kg/day, e.g. 0.25 to 50 μgV/kg/day especially 0.5 to 20 μg V/kg/day, particularly 0.7 to 20 μgV/kg/day. For rats the minimum effective doses lie generally in theranges 10 to 30 mg V/kg for oral administration and 1 to 6 mg V/kg forinjection. Thus, for example, appropriate injection dosages for ratsbis(maltolato)oxovanadium(IV) may be about 15 mg V/kg and appropriateoral dosages 150-300 mg/kg.

The compositions, if in solution form preferably contain the vanadiumcompounds at concentrations of 0.1 mM to 10M, especially 0.2 mM to 1M,particularly 1.6 to 3.2 mM.

Where the compositions are to be injected, the carrier for the vanadiumcompound may conveniently be aqueous methyl cellulose containing about1% methyl cellulose.

BRIEF DESCRIPTION OF THE DRAWINGS

Efficacy of vanadium treatment according to the invention will bedescribed below with reference to the accompanying drawings in which:

FIG. 1 relates change in weight with time;

FIG. 2 shows average blood glucose values in mmol/l (over time);

FIG. 3 shows the daily food consumption;

FIG. 4 shows daily fluid consumption;

FIGS. 5 and 6 show the effects of vanadyl sulphate on blood pressure;and

FIG. 7 shows the effect of bis(maltolato)oxovanadium (IV) on bloodpressure.

The following non-limiting examples are provided to illustrate theinvention further,

EXAMPLE 1

Bis(maltolato)oxovanadium(IV) (BMOV)

The compound bis(maltolato)oxovanadium(IV) (hereinafter BMOV) wasprepared nearly quantitatively by combining maltol(3-hydroxy-2-methyl-4-pyrone) and vanadyl sulfate in hot or boilingwater at a ratio of 2 to 1. The pH of the solution was raised to 8.5 andthe solution was refluxed overnight. The product was a deep purple-greencompound that precipitated and was filtered after cooling the reactionmixture to ambient temperature. The compound is birefringent.

The compound is characterised as follows:

Its elemental analysis is correct for C₁₂ H₁₀ O₇ V; % calculated(found): C 45.45 (45.60): H 3.18 (3.30) and its electron impact messspectrum is also consistent: m/e=317 (M⁺). The infrared spectrum showsabsorptions (KBr disk) characteristic of the maltolato anion bound to ametal cation (1610, 1570, 1560, 1465 cm⁻¹) and characteristic of thevanadyl group V=O (995 cm⁻¹). It has a magnetic moment in the solidstate of 1.76 B.M. indicating one unpaired electron; however, it gives aclear ¹ H NMR spectrum in D₂ O or d₄ -methanol (δ2.5 (s,6H), 6.55(d,2H),8.15(d,2H)) and a clear ⁵¹ V NMR spectrum in D₂ O(-496 ppm). Thecompound is quite water-soluble (about 7 mM, 2mg mL⁻¹). Its log p valueis 0.12.

EXAMPLE 2

Bis(kojato)oxovanadiumIV) (vanadyl koate)

VOSO₄.5H₂ O (Aldrich, 2.50 g, 9.88 mmol) was dissolved in 10 mL hotwater, and the solution was degassed with Ar for 10 minutes and added to10 mL of an aqueous solution of kojic acid(2-hydroxymethyl-5-hydroxy-γ-pyrone) (Sigma, 2.88 g, 20.3 mmol) andNaOAc.3H₂ O (Fisher, 2.97 g, 21.8 mmol), which had also been degassed.After refluxing under Ar overnight, a blue precipitate was isolated byvacuum filtration using a Schlenk filtering funnel and dried overnightin vacuo. The yield was 2.69 g (78% based on V).

The compound is characterised as follows:

Its elemental analysis is correct for C₁₂ H₁₀ O₉ V; % Calculated(found): C, 41.28 (41.06); H, 2.89 (2.89) and its fast atom bombardmentmass spectrum is also consistent: m/e=350 (MH⁺). The infrared spectrumshows absorptions (KBr Disk) characteristic of the kojato anion bound toa metal cation (1610, 1550, 1500, 1470 (ν_(c=o), ν_(c=c)) cm⁻¹) andcharacteristic of the vanadyl group V=O (980 cm⁻¹). It has a magneticmoment in the solid state of 1.76 B.M., indicating one unpairedelectron. No ¹ H NMR signal was observed in a chemical shift range from-15 to +20 ppm in a freshly prepared D₂ O solution. The compound isquite water-soluble (about 45 mM, 16 mg/mL). Its p value is 0.012.

The following experiments were conducted in rats with BMOV, vanadylkojate and vanadyl sulphate, the first two as prepared above.

EXAMPLE 3

Initial experiments were carried out to determine pharmacologicaleffectiveness of BMOV. Using male rats, made diabetic by the injectionof streptozoticin (STZ) at a dose of 60 mg/kg i.v., BMOV was initiallygiven by intraperitoneal (i.p.) injection as a suspension in 1% methylcellulose.

1. Injection

Nine out of the twelve rats given 15 mg/kg i.p. (0.05 mmol/kg) respondedto the compound with a decrease in blood glucose. Two animals developedhypoglycemia.

2. Oral Administration

a. Drinking. Administration of the vanadyl compound in the drinkingwater at doses of 0.46-0.92 mmol/kg (150-300 mg/kg, using concentrationsof 0.5-1.3 mg/mL) reduced blood glucose in four diabetic rats into thenormal range. Fluid intake was also decreased to normal in theseanimals.

b. Gavage. Six out of six diabetic rats responded to the vanadylcompound with a decrease in blood glucose when BMOV was given by gavagein a dose of 160 μmol/kg over 40 days. The peak fall in blood glucoseoccurred 5 hours after administering the drug. The blood glucosereturned to diabetic levels usually within 12 hours.

Based on these preliminary studies, more detailed studies wereundertaken to determine the minimum effective dose of BMOV required tomaintain normal blood glucose in diabetic animals.

EXAMPLE 4

Prolonged administration

BMOV was administered to normal and diabetic rats in drinking water.

The study was composed of 4 groups of animals. Control (8 animals),Control-Treated (11 animals), Diabetic (11 animals) and Diabetic-Treated(12 animals). The diabetic state was induced by injecting STZ at 60mg/kg dissolved in 0.9% NaCl I.V. via the tail vein to anaesthetisedrats. The two control groups were injected with 0.9% NaCl I.V. throughthe tail vein. The diabetic state was determined with a "Testape"™ testat 3 days post-injection and later confirmed with a glucometer test.Blood glucose and insulin assays were carried out post-injection overthe course of the study. Treatment according to the invention wasstarted 1 week after determination of the diabetic state.

Treated diabetic animals received between 0.3 and 0.5 mmol/kg of thecompound/day in drinking water over a 77 day period. Treated controlanimals received a slightly lower dose (0.2-0.3 mmol/day) over the sameperiod. The concentration of BMOV in the drinking water was variedbetween 1.6 and 3.2 mM. The reason for the differing doses in the twosets of animals is that the two groups drank different amounts of waterdaily; it was difficult to attain the same dose in both groups.

With the above treatment regimen, the following was noted:

1. The weight gain over the 77 day period is shown in FIG. 1. Asindicated above, 4 groups of animals were studied, but thediabetic-treated group was sub-divided to diabetic-treated responders (8animals) and diabetic-treated non-responders (4 animals). Curve 1 is thecontrol group, curve 2 the control-treated group, curve 3 the diabeticgroup, curve 4 is the diabetic-treated responders and curve 5 is thediabetic-treated non-responders. Initially, there was a significantdifference only between the two control groups with respect to the threediabetic groups. However, by day 7 there was a significant differencebetween the two diabetic-treated groups with respect to all othergroups. By day 28, the diabetic-treated non-responder group wassignificantly different from the other 4 groups and there was no longera significant difference between the diabetic group and the diabeticresponder group. By day 56, there was a significant difference betweenthe control group and the control treated group. Treatment began with a3.17 mM solution of the compound. On day 6, the concentration wasreduced to 1.58 mM (0.5 mg/ml). On day 24, the concentration wasincreased to 2.37 mM (0.7 mg/ml). At this point 8 out of the 12 animalswere responding to the compound.

The control treated animals showed a significantly decreased weight gainbeginning at day 56. The decrease was correlated with the decrease infood intake.

2. FIG. 2 shows average blood glucose values (mmol/l) for the 5 groupsbased on weekly blood glucose determinations. The 5 groups were as inFIG. 1. Initially, there was a significant difference between the twocontrol groups with respect to all three of the diabetic groups. By day7, there was a significant difference between the diabetic group withrespect to both diabetic-treated groups. By day 14, the diabetic-treatedresponder group was euglycemic; however, on day 18 there was an increasein blood glucose levels for this group due to the necessity to withholdtreatment for a few days to treat hypoglycemia, which developed inseveral animals. The diabetic-treated non-responder group consists ofrats which exhibited marked fluctuations in glucose values.

Thus, eight of the twelve treated diabetic rats had their blood glucosevalues lowered from 20+mM to less than 10 mM from day 7 onwards. Four ofthe twelve rats had blood glucose readings ranging from 6-20 mM on anygiven day. These rats are the non-responders. By day 24, diabetic ratsthat responded to the compound had normal blood glucose.

3. FIG. 3 demonstrates the daily food consumption per rat. The rats wereallowed free access to food with 2-3 rats per cage for the fourtreatment groups. The control group is curve 1, the diabetic group iscurve 2, the control-treated group is curve 3 and the diabetic-treatedgroup is curve 4. For the first approximately 50 days of treatment, theonly significant difference occurred between the diabetic group withrespect to all of the other groups. However, from day 63 on, there wasalso a significant difference between the control-treated group and allthe other groups. There was no significant difference between thecontrol and the diabetic-treated groups at any time.

FIG. 4 shows the daily fluid consumption per rat. The rats had freeaccess to fluids with 2-3 rats per cage for the four treatment groups.The control group is curve 1, the control-treated group is curve 2, thediabetic group is curve 3 and the diabetic-treated group is curve 4.Initially, the only significant difference occurred between the diabeticgroup with respect to all of the other treatment groups. However by day63, there was also a significant difference between the control treatedgroup and all the other treatment groups. There was no significantdifference in fluid consumption between the control and thediabetic-treated groups throughout.

FIGS. 3 and 4 illustrate that control of blood glucose was accompaniedby a reduction in food intake in the diabetic rats from greater than 50grams per day to about 30 grams per day (28±1.6 on day 77). There was aslight reduction in food intake (from 29±0.1 to 25.5±0.3) in controlrats treated with the compound. Fluid intake fell from about 275 ml/ratin the diabetic group to about 60 ml/rat in the diabetic treated group.There was also a decrease in fluid intake in the control treated groupcompared with control rats (62.7±7.4 vs 33.6±7.2 ml on day 77). Asstated above, the decrease in food and water intake correlates with thedecrease in weight gain in control animals.

4. Treatment with BMOV decreased weight gain in control animals (200 gvs 250 g for control over the 77 day period). Diabetic-treated animalsgained almost exactly the same weight (140 g) as diabetics, despite thedecrease in food intake; thus weight gain in diabetic-treated animalslagged behind that of control groups animals.

5. Insulin values in control treated rats decreased to the same value asthose for diabetic animals (approximately 22 μ/ml) and weresignificantly lower than those of control (35.8±1.2 μ/ml) as shown inTable I:

                  TABLE I                                                         ______________________________________                                        Insulin Values, μU/ml (Day 28 of BMOV study)                               Control Control-Treated                                                                            Diabetic   Diabetic-Treated                              ______________________________________                                        35.8 ± 1.2                                                                         21.6 ± 1.2                                                                              21.4 ± 2.6                                                                            22.0 ± 1.6                                 ______________________________________                                    

6. Plasma triglyceride and cholesterol values in diabetic animals wererestored to control values by treatment with BMOV as shown in Table II:

                                      TABLE II                                    __________________________________________________________________________    Lipid Values in BMOV Study                                                                 Control                                                                             Diabetic-Treated                                                                       Diabetic-Treated                                         Control                                                                             Treated                                                                             Responders                                                                             Non-Responders                                                                         Diabetic                                 __________________________________________________________________________    Cholesterol mmol/l Means ± S.E.M.                                          Pretreatment                                                                         1.40 ± 0.03                                                                      1.64 ± 0.08                                                                      1.67 ± 0.10                                                                         1.51 ± 0.07                                                                         1.58 ± 0.10                           (Day before                                                                          (8)   (8)   (7)      (4)      (11)                                     treatment                                                                     started)                                                                      Week 6 1.37 ± 0.06                                                                      1.60 ± 0.06                                                                      1.58 ± 0.11                                                                         1.48 ± 0.09                                                                         2.65 ± 0.28*                                 (8)   (10)  (8)      (4)      (11)                                      *Diabetic untreated is significantly different from all other groups by       ANOVA followed by either Fishers', NewmanKeuls' or Duncans' test.        

    Triglyceride mmol/l Means ± S.E.M.                                         Pretreatment                                                                         1.27 ± 0.08                                                                      1.21 ± 0.14                                                                      1.10 ± 0.09                                                                         1.85 ± 0.41*                                                                        1.21 ± 0.08                           (Day before                                                                          (8)   (8)   (8)      (4)      (11)                                     treatment                                                                     started)                                                                       *Diabetic-treated nonresponders are significantly different from all othe     groups by ANOVA followed by either Fishers', NewmanKeuls' or Duncans'         test.                                                                        Week 6 1.81 ± 0.11                                                                      2.04 ±  0.22                                                                     1.70 ± 0.18                                                                         2.31 ± 0.19                                                                         4.14 ± 0.98*                                 (8)   (10)  (8)      (4)      (11)                                     __________________________________________________________________________     *Diabetic-untreated are significantly different from all groups except        diabetictreated nonresponders by ANOVA followed by Fishers' and Duncans'      test, but not by ANOVA followed by NewmanKeuls' test. One rat in this         group had a very high triglyceride value  13.1 mmol/l.                   

7. At the end of 77 days of treatment, 0/8 of the treated diabetic rats,which were controlled by the drug, had cataracts. 5/11 Of the untreateddiabetic animals showed cataracts. One of the four treated animals, notcontrolled by the drug, also had a cataract. The first cataractdeveloped at 60 days in the untreated diabetic group.

EXAMPLE 5

Comparison of BMOV and vanadyl kojate

Using BMOV and Vanadyl Kojate as prepared in Examples 1 and 2 above, therelative efficacy of the two compounds was assessed using rats madediabetic with STZ. Again the animals were divided into responder andnon-responder groups. For a 0.063 mmol V/kg ip injection, BMOV gave a50:50 split between responder and non-responder groups whereas forvanadyl kojate the ratio was 60:40. On oral gavage of 0.55 mmol V/kg theresponder:non-responder ratios were 50:50 and 57:43 respectively (n=10).Results are presented in Table III. However over a 12 day test period,there was a 100% response in terms of blood glucose reduction fordiabetic rats receiving vanadyl kojate orally. Likewise the food andfluid demand by the rats was significantly reduced.

EXAMPLE 6

Blood pressure reduction--Vanadyl sulphate

The insulin resistant spontaneously hypertensive rat was used as theexperimental model and the vanadyl form of vanadium as the experimentalintervention. The spontaneously hypertensive rats (SHR), have been shownto be insulin resistant and hyperinsulinemic as compared to theirgenetic controls, the Wistar Kyoto (WKY) strain. Rats, procured at 4weeks of age, were divided

                                      TABLE III                                   __________________________________________________________________________    Comparison of the plasma glucose levels between the acute time course         experiments                                                                   for BMOV (n = 8) and vanadyl kojate (N = 10)                                  BMOV                    Vanadyl Kojate                                        I.P. (Injection                                                                             oral Gavage)                                                                            I.P. Injection                                                                          Oral Gavage                                 (0.063 mmol/kg)                                                                             (0.55 mmol/kg)                                                                          (0.063 mmol/kg)                                                                         (0.55 mmol/kg)                              TIME                                                                              DTR  DTN  DTR  DTN  DTR  DTN  DTR  DTN                                    (Hrs)                                                                             (50%)                                                                              (50%)                                                                              (50%)                                                                              (50%)                                                                              (60%)                                                                              (40%)                                                                              (57%)                                                                              (43%)                                  __________________________________________________________________________    0   17.51 ±                                                                         19.42 ±                                                                         18.09 ±                                                                         19.31 ±                                                                         17.94 ±                                                                         20.86 ±                                                                         15.75 ±                                                                         23.08 ±                                 0.8  0.15 ± 0.72                                                                          0.35 0.41 0.28 0.55 1.27                                   1   14.77 ±                                                                         18.82 ±                                                                         14.55 ±                                                                         18.05 ±                                                                         14.75 ±                                                                         18.55 ±                                                                         12.5 ±                                                                          21.18 ±                                 2.0  0.8  1.96 0.46 0.44 0.42 1.46 1.45                                   2   12.65 ±                                                                         18.51 ±                                                                         13.13 ±                                                                         17.57 ±                                                                         10.17 ±                                                                         16.62 ±                                                                         10.1 ±                                                                          21.51 ±                                 2.33 0.79 2.04 0.5  0.47 0.65 0.99 1.72                                   4   10.6 ±                                                                          17.94 ±                                                                         11.68 ±                                                                         16.92 ±                                                                         9.26 ±                                                                          17.37 ±                                                                         7.96 ±                                                                          20.57 ±                                 2.39 0.85 2.07 0.35 0.32 0.23 0.26 1.07                                   6   10.28 ±                                                                         18.08 ±                                                                         9.47 ±                                                                          16.43 ±                                                                         8.73 ±                                                                          16.62 ±                                                                         6.6 ±                                                                           18.2 ±                                  1.76 0.48 2.58 0.43 0.17 0.35 0.35 0.89                                   8   9.08 ±                                                                          17.77 ±                                                                         9.27 ±                                                                          15.02 ±                                                                         7.4 ±                                                                           15.49 ±                                                                         6.87 ±                                                                          19.06 ±                                 1.06 0.59 2.27 1.13 0.12 0.65 0.33 0.96                                   12  9.38 ±                                                                          19.07 ±                                                                         7.01 ±                                                                          17.17 ±                                                                         10.37 ±                                                                         18.24 ±                                                                         6.01 ±                                                                          18.81 ±                                 0.96 0.37 0.57 0.60 0.46 0.45 0.25 0.33                                   24  7.15 ±                                                                          19.01 ±                                                                         6.31 ±                                                                          18.07 ±                                                                         13.28 ±                                                                         18.77 ±                                                                         6.74 ±                                                                          25.0 ±                                  1.51 0.21 0.57  0.74                                                                              0.83 0.49 0.05 0.4                                    __________________________________________________________________________     DTR  Diabetic Treated Responders                                              DTN  Diabetic Treated Nonresponders                                      

into 4 groups: SHR (untreated), SHRV (treated), WKY (untreated), WKYV(treated). Chronic vanadyl sulfate treatment (0.75 mg/ml ad libitum inthe drinking water) was started on the SHRV and WKYV groups at 5 weeksof age. After week 8, when hypertension becomes fully manifest in theSHR, weekly measurements of plasma insulin and systolic blood pressure(tail cuff method) were done on all four groups. Vanadyl, in doses of75-125 mg/kg/day, lowered both plasma insulin and systolic bloodpressure in the SHRV group at all time points from weeks 8-12 (FIG. 5),without causing any change in the plasma glucose levels. No changes wereseen in the control, normotensive WKYV animals.

At week 11, the untreated control SHR and WKY groups from the preventionstudy were further subdivided and half the animals in each group werestarted on oral vanadyl sulfate treatment. This was done to observe thereversal effects of vanadyl, if any, after the SHR had becomehypertensive. Vanadyl reversed hypertension in the SHR treated group(SHRV₁) as well as lowering their plasma insulin to control values, buthad no effect in the Wistar Kyoto rats (WKYV₁) (see FIG. 6). A directblood pressure reading done in all groups at termination validated theearlier indirect measurements. Vanadyl sulfate prevented as well asreversed hypertension in the hyperinsulinemic spontaneously hypertensiverat, a model that closely resembles human essential hypertension.Besides establishing further the role that insulinresistance/hyperinsulinemia may play in the development of high bloodpressure, this study also indicated a possible therapeutic role forvanadyl sulfate in hypertensive, hyperinsulinemic subjects. Nogastrointestinal, renal or hepatic toxicity of vanadyl was observed inthe treated animals (at doses of 75-125 mg/kg/day) during the entireexperimental period.

In summary, FIG. 5 shows that vanadyl treatment prevents the onset ofhypertension in rats that normally become hypertensive during the firstmonths of life. No change is observed in the Wistar rats which do notnormally become hypertensive.

FIG. 6 shows that once SHR have been allowed to become hypertensive thatthe vanadyl treatment will reduce the blood pressure. Again, no effectis observed in the control Wistar rats.

The conclusion is that vanadyl is useful as a prophylactic and as atherapeutic in hypertension. Another advantage is that vanadyl has noadverse effect on normal animals (i.e. it did not produce hypotension innormal animals).

EXAMPLE 7

Blood pressure reduction--BMOV

11 SHR and 12 WKY rats (all male) were procured at 4 weeks of age fromCharles River, Canada. The animals were divided into four experimentalgroups: SHR (untreated n=5), SHRO (BMOV treated n=6), WKY (untreatedn=8) and WKYO (BMOV treated n=4). Chronic BMOV treatment was commencedon the SHRO and WKYO groups at 5 weeks of age. The rats were given BMOV(0.75 mg/ml) ad libitum in the drinking water. A concentration of 0.75mg/ml was chosen since previous laboratory studies indicated that thisconcentration was sufficient to lower plasma insulin levels in nondiabetic rats, while allowing them to gain weight at rates that weresimilar to untreated control animals.

Once at week 5 and then starting at week 8, weekly measurements of bloodpressure were done on all groups for the next 3 weeks. Blood sampleswere also collected via the tail vein during the weeks mentioned above.These were centrifuged and plasma was collected for subsequent glucoseand insulin analyses. Chronic blood pressure measurements were done onconscious rats, using the tail cuff method without external preheating.Initial experiments to validate the tail cuff method by comparing thereadings obtained with it to those obtained by direct arterialcannulation were conducted. It was found that systolic blood pressuremeasured with this technique was similar to that obtained by directarterial cannulation.

BMOV caused a reduction in systolic blood pressure in the treated SHROrats, without having any effect on the normotensive WKYO controls (FIG.7). The decrease in systolic blood pressure after BMOV treatment wasmarked (25-30 mmHg) and persisted throughout the entire experimentalperiod. Thus, BMOV was able to prevent the development of high bloodpressure in the SHR.

The present invention provides a pharmaceutical composition useful forthe treatment of diabetes (especially type II diabetes), as an appetitesuppressant, or as an antihypertensive. The active compounds areabsorbed across the gastrointestinal barrier and deliver the vanadyl ionto the bloodstream, where the insulin-mimetic properties of vanadium canbe expressed. In contrast to insulin, the compositions are active whentaken by mouth, and represent a significant advance in diabetes therapy.The compositions are also useful as orally active appetite suppressantsand would be effective in treating obesity. The majority of diabeticsare overweight, but obesity in general is a significant problem inwestern society, leading to an increase in morbidity and mortality.Morbid obesity is a health endangering condition. A drug that willsuppress appetite, leading to weight loss, is of significant value. Theactive ingredients of the present invention are simple, monomericspecies in the solid state. They are easily prepared, easilyadministered, relatively stable, and highly effective in lowering bloodglucose, in suppressing appetite and in combatting hypertension.

EXAMPLE 8

Bis(3-oxy-1,2-dimethyl-4pyridinonato)oxovanadium (IV), VO(dPP)₂

To a solution of maltol (2.10 g, 16.7 mmol) and VOSO₄.5H₂ O (2.01 g, 8.0mmol) in 20 mL hot water was added 20 mL 40% methylamine in water (26mmol) and the pH of the solution was decreased from 11.7 to 9.9 byaddition of 2N H₂ SO₄. The solution was refluxed for 8 hours. A grayblue solid was collected by filtration and washed several times with hotwater. The yield was 2.56 g (94%). The solid state magnetic moment was1.77 BM.

IR (cm¹): 965, 1430(w), 1450, 1490, 1550, 1605

Elemental analysis: C₁₄ H₁₆ N₂ O₅ V Calc. (%): C 48.99 H 4.70 N 8.16Found (%): C 48.56 H 4.65 N 8.38

Mass spect. (FAB): m/e=344 (HVOL₂ ⁺, base peak), 343 (VOL₂ ⁺)

EXAMPLE 9

Bis(2-hydroxymethyl-5-oxy-1-methyl-4-pyridinonato) oxovanadium(IV),VO(hmp)₂

To a solution of kojic acid (2.80 g, 19.7 mmol) in 40 mL hot water wasadded 20 mL 40% methylamine in water (26 mmol) and VOSO₄.5H₂ O (2.47 g,9.8 mmol) in 20 mL hot water. The pH of the solution was decreased from12.8 to 11.0 by addition of 2N H₂ SO₄. The solution was refluxed underAr for 8 hours. A blue solid was collected by filtration and washedseveral times with hot water. The yield was 2.45 g (67%). The solidstate magnetic moment was 1.74 BM.

IR (cm⁻¹): 970, 1300, 1450, 1510, 1560(m), 1610(m)

Elemental analysis: C₁₄ H₁₆ N₂ O₇ V Calc. (%): C 44.81 H 4.30 N 7.47Found (%): C 45.00 H 4.39 N 7.47

Mass spect. (FAB): m/e=376 (HVOL₂ ⁺, base peak), 375 (VOL₂ ⁺)

EXAMPLE 10

Bis[2-(2'-oxyphenyl)-2-oxaxolinato]oxovanadium(IV), VO(oz)₂

To a solution of 2-(2'-hydroxyphenyl)-2-oxazoline (prepared according toliterature) (0.31 g, 1.90 mmol) and NaOAc.3H₂ O (0.27 g, 1.95 mmol) inCH₃ OH (10 mL) was added VOSO₄.3H₂ O (0.20 g, 0.92 mmol) in 11 mL of CH₃OH:H₂ O (10:1) solution. A gray-blue solid was collected by filtration.Recrystallization of the solid from CH₂ Cl₂ yielded large blue crystals.The yield was 0.27 g (75%). The solid state magnetic moment was 1.84 BM.

IR (cm⁻¹): 990, 1595(m), 1620(m) UV-vis (in CH₂ Cl₂) λ_(max) nm (ε,M⁻¹cm⁻¹): 597 (47), 543 (45), 409 (sh,111)

Elemental analysis: C₁₈ H₁₆ N₂ O₅ V Calc. (%): C 55.25 H 4.12 N 7.16Found (%): C 55.12 H 4.17 N 7.08

Mass spect. (EI): m/z=391 (VOL₂ ⁺), 229 (VOL⁺), 163 (L⁺)

Trans orientation of the ligands and vanadium coordination by thephenoxy oxygen and the oxazoline nitrogen was confirmed by X-raycrystallography at 21° C.

EXAMPLE 11

Bis[2-(2'-oxyphenyl)-2-thiazolinato]oxovanadium(IV), VO(tz)₂ -0.5H₂ O

The title product was prepared analogously to that of Example 10 using2-(2'-hydroxyphenyl)-2-thiazoline (0.34 g, 1.90 mmol) (preparedaccording to literature), VOSO₄.3H₂ O (0.20 g, 0.92 mmol) and NaOAc.3H₂O (0.27 g, 1.95 mmol). Recrystalization from CH₂ Cl₂ yielded largeyellow-green crystals. The yield was 0.32 g (82%). The solid statemagnetic moment was 1.80 BM.

IR (cm⁻¹): 980, 1540, 1570, 1600 UV-vis (in CH₂ Cl₂) λ_(max) nm (ε, M⁻¹cm⁻¹): 595(53), 537(66), 437 (sh, 179)

Elemental analysis: C₁₈ H₁₇ N₂ O₃.5 S₂ V (hemi hydrate) Calc. (%): C50.00 H 3.98 N 6.48 Found (%): C 50.42 H 3.83 N 6.47

Mass spect. (EI): m/z=423 (VOL₂ ⁺), 245 (VOL⁺), 179 (L⁺)

Trans orientation of the ligands and vanadium coordination by thephenoxy oxygen and the oxazoline nitrogen was confirmed by X-raycrystallography at 21° C.

EXAMPLE 12

Bis(benzohydroxamato)oxovanadium(IV), VO(bz)₂

VOSO₄.3H₂ O (0.20 g, 0.92 mmol) in 10 mL water was added dropwise to asolution of benzohydroxamic acid (Sigma, 0.26 g, 1.90 mmol) in 20 mL hotwater. A purple solid precipitated. The pH of the suspension was raisedfrom 1.7 to 7.4 by the slow addition of 0.5N NaOH. The suspension wasthen stirred for 1.5 hours. The purple solid was collected by filtrationyielding 0.22 g (71%) of the product. The solid state magnetic momentwas 1.72 BM.

IR (cm⁻¹): 995, 1440, 1480, 1510, 1570, 1600, 3200 (b)

Elemental analysis: C₁₄ H₁₂ N₂ O₅ V Calc. (%): C 49.57 H 3.57 N 8.26Found (%): C 49.37 H 3.66 N 8.02

Mass spect. (FAB): m/e=340 (HVOL₂ ⁺), 339 (VOL₂ ⁺, base peak)

EXAMPLE 13

Bis(benzohydroxamato)methoxooxovanadium(V), VO(OCH₃) (bz)₂

VO(bz)₂ (0.11 g. 0.32 mmol) was dissolved in 10 mL of warm methanol (ca.35° C.) and then stirred for 2 hours. A brick-red microcrystalline solidprecipitated after the addition of 10 mL of water. The product wascollected by filtration and washed several times with water. The yieldwas 0.065 g (54%). The solid state magnetic moment was 0.

IR (cm⁻¹): 960, 1440(m), 1480, 1520(b), 1600, 3200(b) UV-vis (inmethanol) λ_(max) nm (ε, M⁻¹ cm⁻¹): 441(2000) ⁵¹ V NMR in CH₂ Cl₂δ(ppm): -425 ¹ H NMR δ(ppm): 3.34 (3H), 7.40 (2H, J=7.5 Hz), 7.49 (1H,J=7.5 Hz ), 7.73 (2H, J=7.1 Hz )

Elemental analysis: C₁₅ H₁₅ N₂ O₆ V Calc. (%): C 48.66 H 4.08 N 7.57Found (%): C 48.46 H 4.03 N 7.54

Mass spect. (FAB): m/e=339 (VOL₂ ⁺)

EXAMPLE 14

Biz(benzohydroxamato)ethoxooxovanadium(V), VO(OC₂ H₅)(bz)₂

VO(bz)₂ (0.10 g. 0.30 mmol) was dissolved in 10 mL of hot ethanol andstirred for 2 hours. A golden-red solid precipitated upon slowevaporation of solvent. The product was collected by filtration andwashed several times with water. The yield was 0.058 g (52%). The solidstate magnetic moment was 0.

IR (cm⁻¹): 970, 1450, 1490, 1520(b), 1550(b), 1600, 3200(b) UV-vis (inethanol) λ_(max) nm (ε, M⁻¹ cm⁻): 446(2400) ⁵¹ V NMR in ethanol δ(ppm):-411 ¹ H NMR δ(ppm): 1.17 (3H, J=7.1 Hz), 3.60 (2H, J=7.1 Hz), 7.43 (2H,J=7.5 Hz), 7.52 (1H, J=7.4 Hz), 7.78 (2H, J=7.2 Hz )

Elemental analysis: C₁₆ H₁₇ N₂ O₆ V Calc. (%): C 50.01 H 4.46 N 7.29Found (%): C 50.32 H 4.54 N 7.16

Mass spect. (FAB): m/e=339 (VOL₂ ⁺)

EXAMPLE 15: (Comparative)

Bis(acetylacetonate)oxovanadium(IV), VO(acac)₂

5 g of ammonium metavanadate (NH₄ VO₃) was heated in a dry 250 mL beakerwith constant stirring until the compound turned orange. A solutioncontaining 12 mL H₂ O, 9 mL concentrated H₂ SO₄ and 25 mL ethanol wasadded slowly. The solution was heated, the colour changing fromyellow-red to dark green-blue. It was allowed to cool slightly and wasthen filtered. 13 mL of acetylacetone was added to the filtrate whichwas then transferred to a 400 mL beaker before being neutralized bycareful slow addition of 20 g Na₂ CO₃ dissolved in 125 mL H₂ O. Theprecipitate formed was removed by filtration, washed with H₂ O, dried inair, dissolved in 50 mL dichloromethane and filtered. Anhydrous MgSO₄was added to the filtered solution which was then stirred for 30minutes, filtered and evaporated down under reduced pressure to yieldVO(acac)₂ as a blue crystalline material.

Yield 7 g (60%).

Elemental analysis: Calc. C 45.30% H 5.32% Found C 45.31% H 5.26%

The complex shows an infrared band for ν(V=0)=1000 cm⁻¹ and the magneticmoment of 1.71 BM is consistent with a single unpaired electron.

EXAMPLE 16: (Comparative)

Bis(salicylaldehyde)oxovanadium(IV), VO(Sal)₂

Methanol, ethanol and water were degassed by being vigorously stirredfor 1514 20 minutes while argon was bubbled through. Under a flow orargon, 6.1 g of salicylaldehyde was dissolved in 50 mL of degassedmethanol. 5.425 g of vanadyl sulphate trihydrate (VOSO₄.3H₂ O) wasdissolved in 25 mL degassed water and 25 mL degassed ethanol. Theresultant blue solution was added to the colourless salicyladehydesolution to give a green solution which was stirred at 5° C. for threedays. 10 g of anhydrous sodium acetate was added under argon resultingin a rapid colour change from emerald green to yellow-brown. Thissolution was stirred at 5° C. for a further two days by which time ayellow-green precipitate had formed. The precipitate was removed byfiltration, washed with water (3×10 mL) and then diethylether (4×15 mL)and dried under reduced pressure. The yield was 4.4 g (60%).

Elemental analysis: Calc. (VO(Sal)₂) C 54.39% H 3.26% Calc. (VO(Sal)₂.H₂O) C 48.71% H 3.70% Found C 41.60% H 3.40%

Repeated performance of the preparation gave similar elemental analysisresults.

The complex showed an infrared band ν(V=0)=960 cm⁻¹.

EXAMPLE 17

Comparative testing

Six male wistar rats weighing between 175-200 g were obtained from alocal source. Diabetes was induced in all animals by a singleintravenous injection of streptozotocin (STZ) 60 mg/kg in 0.9% NaCl viathe tail vein. Three days after STZ injection, blood was collected fromthe tail by nicking the tail tip and expressing the blood intoheparinized capillary tubes. Blood was centrifuged at 20,000 g for 10minutes to separate the plasma. Glucose analysis was done immediately onthe plasma sample using a Boehringer Mannheim kit. Plasma glucose levelsgreater than 13 mM were taken as diabetic. One week after STZ injectionanimals were randomly divided into 3 pairs of rats. Each pair of ratsreceived by oral gavage 1 mmol/kg of BMOV or VO(Sal)₂ or VO(acac)₂,suspended in 3% acacia. Blood was collected for plasma glucose analysisas described above immediately prior to dosing and at 2, 4, 6, 8, 12 and24 hours after administration.

The plasma glucose levels (mM) detected for the three test complexes areset out in the Table below

    ______________________________________                                                 Time (Hours)                                                         Drug    Rat    0      2    4    6    8     12   24                            ______________________________________                                        VO(Sal).sub.2                                                                         1      21.09  22.77                                                                              20.18                                                                              20.67                                                                              21.57 19.24                                                                              18.73                                 2      21.12  22.31                                                                              21.74                                                                              21.85                                                                              21.59 19.74                                                                              18.64                         BMOV    3      23.02  23.87                                                                              22.27                                                                              21.21                                                                              20.26 9.97 0.8                                   4      23.01  23.15                                                                              23.32                                                                              22.09                                                                              19.45 8.73 1.0                           VO(acac).sub.2                                                                        5      23.87  22.91                                                                              22.37                                                                              23.96                                                                              27.19 19.13                                                                              dead                                  6      22.74  24.5 22.89                                                                              22.94                                                                              23.65 18.86                                                                              2.43                          ______________________________________                                    

The normal glucose level for a healthy rat is about 5-6 mM, a level ofabout 13 mM would be considered diabetic and the normal range for STZdiabetic rats is 20-25 mM.

The high gavage dosage of 1 mmol/kg selected for the comparison wasselected to enable any blood sugar lowering effect of the compounds ofComparative Examples 15 and 16 to be detected. For BMOV the preferreddosage to achieve englycermia would have been 0.55 mmol/kg. From theresults set forth in the Table above it is immediately clear that BMOVis superior in blood pressure reducing effect to the compounds ofComparative Examples 15 and 16.

EXAMPLE 18

Ammonium bis(maltolato)dioxovanadate ##STR17##

One equivalent of ammonium vanadate was dissolved in water. Twoequivalents of maltol were added and the mixture was allowed to stirovernight. During this time yellow microcrystals formed. They werefiltered and dried. An 87% yield of the ammonium salt ofbis(maltolato)-dioxovanadate was obtained. Elemental, spectral, andx-ray analysis confirmed the composition and structure.

EXAMPLE 19

Six male Wistar rats, weighing 175-200 gm, were made diabetic by theintravenous injection of 60 mg/kg of streptozotocin dissolved in 0.9%saline via the tail vein. Seven days after the injection the rats werediabetic having an average glucose concentration of 24.20 mM. 0.55mmoles/kg of the ammonium salt of bis(maltolato) dioxovanadate suspensedin 3% acacia was gavaged into the rats. Blood was collected and analyzedfor glucose as a function of time. The table below shows that thecompound was effective in reducing the elevated plasma glucose levels.

    ______________________________________                                        Time (hrs):                                                                             0      1       2    4    8     12   24                              ______________________________________                                        Glucose (mM):                                                                           24.2   24.4    25.5 24.7 22.3  20.1 14.9                            ______________________________________                                    

The present invention provides a pharmaceutical composition useful forthe treatment of diabetes (especially type II diabetes), as an appetitesuppressant, or as an antihypertensive. The active compounds areabsorbed across the gastrointestinal barrier and deliver the vanadyl ionto the bloodstream, where the insulin-mimetic properties of vanadium canbe expressed. In contrast to insulion, the compositions are active whentaken by mouth, and represent a significant advance in diabetes therapy.The compositions are also useful as orally active appetite suppressantsand would be effective in treating obesity. The majority of diabeticsare overweight, but obesity in general is a significant problem inwestern society, leading to an increase in morbidity and mortality.Morbid obesity is a health endangering condition. A drugh that willsuppress appetite, leading to weight loss, is of significant value. Theactive ingredients of the present invention are simple, monomericspecies in the solid state. They are easily prepared, easilyadministered, relatively stable, and highly effective in lowering bloodglucose, in suppressing appetite and in combatting hypertension.

We claim:
 1. A method of combatting elevated blood sugar levels in apatient in need thereof, said method comprising administering to saidpatient bis(maltolato)oxovanadium (IV) in a daily dosage of 0.0007 to2.0 mg vandium/kg bodyweight.
 2. The method as claimed in claim 1wherein an additional antidiabetic drug is also administered to saidpatient.
 3. The method as claimed in claim 2 wherein said additionaldrug is insulin.
 4. The method as claimed in claim 3 whereinadministration is effected orally.
 5. The method as claimed in claim 3wherein administration is effected transdermally.
 6. The method asclaimed in claim 2 wherein said additional drug is a compound of anantidiabetically effective metal.
 7. The method as claimed in claim 6wherein said additional drug is a physiologically tolerable chromiumcompound.
 8. The method as claimed in claim 6 wherein administration iseffected orally.
 9. The method as claimed in claim 6 whereinadministration is effected transdermally.
 10. The method as claimed inclaim 1, wherein administration is effected orally.
 11. The method asclaimed in claim 1, wherein administration is effected transdermally.